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Fleming T.H.,University of Heidelberg | Theilen T.-M.,University of Heidelberg | Masania J.,University of Warwick | Wunderle M.,University of Heidelberg | And 13 more authors.
Gerontology | Year: 2013

Methylglyoxal (MG), the major dicarbonyl substrate of the enzyme glyoxalase 1 (GLO1), is a reactive metabolite formed via glycolytic flux. Decreased GLO1 activity in situ has been shown to result in an accumulation of MG and increased formation of advanced glycation endproducts, both of which can accumulate during physiological aging and at an accelerated rate in diabetes and other chronic degenerative diseases. To determine the physiological consequences which result from elevated MG levels and the role of MG and GLO1 in aging, wound healing in young (≤12 weeks) and old (≥52 weeks) wild-type mice was studied. Old mice were found to have a significantly slower rate of wound healing compared to young mice (74.9 ± 2.2 vs. 55.4 ± 1.5% wound closure at day 6; 26% decrease; p < 0.0001). This was associated with decreases in GLO1 transcription, expression and activity. The importance of GLO1 was confirmed in mice by inhibition of GLO1. Direct application of MG to the wounds of young mice, decreased wound healing by 24% compared to untreated mice, whereas application of BSA modified minimally by MG had no effect. Treatment of either young or old mice with aminoguanidine, a scavenger of free MG, significantly increased wound closure by 16% (66.8 ± 1.6 vs. 77.2 ± 3.1%; p < 0.05) and 64% (40.4 ± 7.9 vs. 66.4 ± 5.2%; p < 0.05), respectively, by day 6. As a result of the aminoguanidine treatment, the overall rate of wound healing in the old mice was restored to the level observed in the young mice. These findings were confirmed in vitro, as MG reduced migration and proliferation of fibroblasts derived from young and old, wild-type mice. The data demonstrate that the balance between MG and age-dependent GLO1 downregulation contributes to delayed wound healing in old mice. Copyright © 2013 S. Karger AG, Basel.

Yusenko M.V.,University of Heidelberg | Ruppert T.,ZMBH | Kovacs G.,University of Heidelberg
International Journal of Biological Sciences | Year: 2010

Renal oncocytomas (RO) and chromophobe renal cell carcinomas (RCC) display morphological and functional alterations of the mitochondria. Previous studies showed that accumulation of mitochondria in ROs is associated with somatic mutations of mitochondrial DNA (mtDNA) resulting in decreased activity of the respiratory chain complex I, whereas in chromophobe RCC only heteroplasmic mtDNA mutations were found. To identify proteins associated with these changes, for the first time we have compared the mitochondrial proteomes of mitochondria isolated from ROs and chromophobe RCCs as well as from normal kidney tissues by two-dimensional polyacrylamide gel electrophoresis. The proteome profiles were reproducible within the same group of tissues in subsequent experiments. The expression patterns within each group of samples were compared and 81 in-gel digested spots were subjected to nanoLC-MS/MS-based identification of proteins. Although the list of mitochondrial proteins identified in this study is incomplete, we identified the downregulation of NDUFS3 from complex I of the respiratory chain and upregulation of COX5A, COX5B, and ATP5H from complex IV and V in ROs. In chromophobe RCCs downregulation of ATP5A1, the alpha subunit of complex V, has been observed, but no changes in expression of other complexes of the respiratory chain were detected. To confirm the role of respiratory chain complex alterations in the morphological and/or functional changes in chromophobe RCCs and ROs, further studies will be necessary. © Ivyspring International Publisher.

News Article | February 15, 2017

Brian Luke, a Group Leader at the Institute of Molecular Biology (IMB) in Mainz, has been awarded a prestigious Heisenberg Professorship from the Deutsche Forschungsgemeinschaft (DFG, German Research Foundation). Brian Luke is now jointly appointed as Professor at Johannes Gutenberg University Mainz (JGU) and Adjunct Director at the Institute of Molecular Biology (IMB), where he will continue to investigate the structure and function of telomeres. Telomeres are protective caps found at the ends of linear chromosomes. Free DNA ends are normally recognised by the cell as being broken and trigger a DNA damage response, which stops the cell from dividing and propagating the damage to other cells. At the natural ends of chromosomes, however, telomeres protect the DNA ends from such a response. Problems with telomere function can result in tissue loss due to increased rates of cellular senescence, as well as chromosomal abnormalities associated with ageing. Moreover, cancer cells acquire means to lengthen their telomeres, which allows them to achieve immortality. The Heisenberg Professorship will support Dr Luke's research into multiple aspects of telomere structure and function. His lab will explore the role of a recently-discovered non-coding telomere repeat containing RNA (TERRA), which is transcribed from telomeres and is important for telomere function. Additionally, the Luke group will investigate telomere looping, which is understood to play a role in protecting chromosome ends from degradation. This research will provide valuable insights into how the structure of telomeres is linked to their function both during ageing and in cancer cells. Brian Luke completed his PhD in Biochemistry at ETH Zurich in 2005 and went on to a postdoc at the École Polytechnique Fédérale de Lausanne (EPFL), where he played a crucial role in the discovery of the non-coding RNA TERRA, which remains one of his main research foci. He established his first independent research group at the Centre for Molecular Biology at the University of Heidelberg (ZMBH), during which time he was elected as an EMBO Young Investigator and received a Chica and Heinz Schaller Award. Luke moved with his group to IMB in 2015. This model from the Luke lab depicts how TERRA functions at telomeres. When telomeres are short, TERRA likely establishes a local heterochromatin state and may promote telomere looping (a). At shortened telomeres (b) and when telomeres are recombining (like in some cancer cells) (c), TERRA levels increase, which promotes telomere lengthening (Rippe and Luke, 2015). The Institute of Molecular Biology gGmbH (IMB) is a centre of excellence in the life sciences that was established in 2011 on the campus of Johannes Gutenberg University Mainz (JGU). Research at IMB concentrates on three cutting-edge areas: epigenetics, developmental biology, and genome stability. The institute is a prime example of a successful collaboration between public authorities and a private foundation. The Boehringer Ingelheim Foundation has dedicated 100 million euros for a period of ten years to cover the operating costs for research at IMB, while the state of Rhineland-Palatinate provided approximately 50 million euros for the construction of a state-of-the-art building. For more information about IMB, please visit http://www. . The Boehringer Ingelheim Foundation is an independent, non-profit organisation committed to the promotion of the medical, biological, chemical and pharmaceutical sciences. It was established in 1977 by Hubertus Liebrecht (1931-1991), a member of the shareholder family of the company Boehringer Ingelheim. With the PLUS 3 Perspectives Programme and the Exploration Grants, the foundation supports independent group leaders. It also endows the internationally renowned Heinrich Wieland Prize as well as awards for up-and-coming scientists. In addition, the foundation pledged to donate 100 million euros to finance the scientific running of the IMB at Johannes Gutenberg University Mainz for ten years. In 2013, the Boehringer Ingelheim Foundation donated a further 50 million euros to Johannes Gutenberg University Mainz. http://www. .

Kramer S.,University of Cambridge | Queiroz R.,ZMBH | Queiroz R.,German Cancer Research Center | Ellis L.,University of Cambridge | And 3 more authors.
Journal of Cell Science | Year: 2010

In trypanosomes, the predominant mechanisms of regulation of gene expression are post-transcriptional. The DEAD-box RNA helicase DHH1 was identified in a screen for gene products that are necessary for the instability of the GPI-PLC mRNA in insect-stage trypanosomes. Expression of an ATPase-deficient dhh1 mutant caused a rapid growth arrest associated with a decrease in polysomes, an increase in P-bodies and a slight decrease in average mRNA levels. However, the effect of dhh1 mutant expression on both turnover and translational repression of mRNAs was selective. Whereas there was little effect on the stability of constitutive mRNAs, the control of a large cohort of developmentally regulated mRNAs was reversed; many mRNAs normally downregulated in insect-stage trypanosomes were stabilized and many mRNAs normally upregulated decreased in level. One stabilised mRNA, ISG75, was characterised further. Despite the overall decrease in polysomes, the proportion of the ISG75 mRNA in polysomes was unchanged and the result was ISG75 protein accumulation. Our data show that specific mRNAs can escape DHH1-mediated translational repression. In trypanosomes, DHH1 has a selective role in determining the levels of developmentally regulated mRNAs.

PubMed | ZMBH
Type: Journal Article | Journal: The EMBO journal | Year: 2010

Hydra forced to regenerate a head releases head activator and head inhibitor during the first hours after cutting to induce head-specific growth and differentiation processes. Analysis of the size distribution demonstrated that the head-activator peptide is co-released with (a) large molecular weight carrier molecule(s) to which it is non-covalently bound. The carrier-bound head activator is fully active on Hydra indicating that a carrier does not hinder the interaction with receptors. In contrast to this the head inhibitor is released in its naked, low molecular mass form. The association or non-association with a carrier molecule results in marked differences in biological properties. The head activator has a short range of action, but a long half-life, the head inhibitor has a global range of action, but a short half-life. These results provide a plausible explanation why two antagonistically acting substances, although they are released from the same site and simultaneously nevertheless can give rise to a well-defined temporal and spatial pattern of differentiation as occurs, for example, during head regeneration in Hydra.

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